The search for improved pain-killing or pain-management agents with fewer drawbacks and side-effects is perennial, and despite recent advances in pharmacology, there are still situations in which no fully satisfactory approach is yet known.
Natural opiates, such as codeine and in particular morphine, have been used as pain-killers for thousands of years. However, to be effective, they must generally be ingested, inhaled or (more recently) injected into the bloodstream. They thus tend to operate throughout the body, rather than it being possible to localise their effect. Additionally, the opiates tend to have side-effects on brain chemistry; the narcotic, perception-modifying and addictive properties of morphine and related compounds are notorious. Lethal doses can also be dangerously close to effective doses. Opiates tend therefore to be restricted to essential uses only, where their effectiveness outweighs their drawbacks.
Opioids are a broader class of compounds. Opioids include the naturally-occurring opiates, as well as semi-synthetic compounds made by chemical modification of opiates (e.g. hydromorphone, oxycodone, and buprenorphine); fully synthetic compounds (e.g. fentanyl, pethidine and methadone); and by some classifications, endogenous naturally-generated body chemicals such as endorphins. The fully-synthetic opioids include compounds having a high degree of structural similarity to natural opiates, as well as compounds that have different structural “backbones”, but which nevertheless appear to operate in conjunction with similar receptors and/or have a similar mode of action to opiates.
Except in a few limited circumstances, opioids have not found widespread use when topically applied, or against less severe levels of pain.
A part of the human or animal body with specific problems in respect of pain management is the eye. Whether for physiological reasons (the eye has a far greater density of nerve fibres than skin), psychological reasons or both, the eye is usually a peculiarly sensitive area. The tissues of the eye also tend to have a structure not found elsewhere in the body. For example, the epithelial cells on the surface of the cornea tend to have a flattened profile, compared to corresponding cells of the outer layers of the skin, and they are also non-keratinising, i.e. they do not generate the keratin filaments that strengthen the outer layer of the skin.
There are also specific problems associated with the eye, a major issue being that many of the pharmaceuticals used in the treatment of eye conditions tend to cause at least irritation of the eye and its surrounds, and often distinct pain (while for many patients pain tolerances in and around the eye are in any case to be low).
The human eye, like the eyes of most terrestrial vertebrate animals, requires considerable lubrication and hydration in order to allow smooth movement of the eye within its socket and of the eyelid across the eye, and to maintain clarity of vision. This is generally achieved by the secretion of tears from glands adjacent the eye. Tears also help to keep the eye clear of foreign bodies and irritant materials, since these usually cause an increased flow of tears, which in conjunction with increased rates of blinking, helps to wash away the cause of the irritation.
One eye condition of particular concern is “dry-eye” (also referred to xerophthalmia or keratoconjunctivitis sicca) in which insufficient tears are produced to lubricate and hydrate the eye, eyelids and eye socket fully and/or tear production cannot increase in the normal manner in response to irritation of the eye. A related, more common problem is “dry-eye syndrome”, also known as keratoconjunctivitis sicca, a condition in which the eyes do not make enough tears, or the tears evaporate too quickly. This may produce anything from mild discomfort to significant levels of pain, sufficient to affect a sufferer's day to day life.
Another eye condition of concern is blepharitis. Blepharitis is a condition in which the rims of the eyelids become inflamed (red and swollen) which can result in symptoms such as: burning, soreness or stinging in the eyes; crusty lashes; and/or itchy eyelids. Meibomitis or meibomian gland dysfunction is a form of blepharitis. Dysfunction and inflammation of the sebaceous glands on the margins of the eyelids (the meibomian glands) causes a reduced production of the oily substances (e.g. lipids) needed to keep the eye lubricated. The substance that is produced is more viscous and less effective at lubricating the eye.
In such conditions in which the lubrication of the eye is reduced, a frequent complication is that vision becomes blurred.
It is known to use lubricating compositions, such as “artificial tears”, dilute solutions of water soluble polymers (such as sodium hyaluronate, hypromellose and/or carbomer gel) that substitute for the missing natural tears. These will temporarily ease the motion of the eye and improve clarity of vision. However, they do not reduce pain levels in the eye to a significant extent.
If conventional painkillers are administered to reduce pain in the eye, this can yield the unfortunate consequence that any lessening of discomfort leads to the blink rate of the eyelid falling. This reduces the generation of tears further, possibly worsening a “dry-eye” condition, probably retarding recovery from the condition, and making it more probable that adventitious foreign material could enter the eye without being flushed out, thus harming the eye further.
It would be desirable to be able to deal with all forms of localised pain or discomfort in and around the eye by locally-applied painkillers, for example in the form of eye-drops, ointments, gels, and so forth. However, commonly-used topical pain-killers such as NSAIDs (e.g. ibuprofen) appear not to have sufficient effect, while topically applied opiates appear not to have the efficacy of injected opiates. However, the side-effects of effective levels of injected opiates would probably be unacceptable.
U.S. Pat. No. 6,384,043 to Peyman discloses that certain opioids have an analgesic effect on a denuded eye (i.e. an eye in which the epithelial cells have been stripped away as part of a treatment, or have been locally penetrated in the case of an eye injury). However, this effect would appear to occur only where the epithelial layer of cells has been breached, this perhaps allowing penetration of this layer by the opiates. An alternative hypothesis is that this damage to the eye leads to the local appearance of opioid receptors, with which the topically-applied opioids may interact as a preliminary to blocking the transmission of pain signals along the nerves.
Whatever the mechanism involved, it has been found that topically-applied morphine has very little or no analgesic effect when applied to an undamaged eye. Possibly penetration is not occurring, or the necessary receptors are not appearing, or both.
It would hence be of benefit if a topically-applicable analgesic formulation could be devised that would be effective on the eye, whether the eye is damaged or not, particularly in order to reduce pain induced by otherwise satisfactory treatments applied to the eye, or to reduce pain in eye infections and conditions in general.